Overall Abstract The goals of the Endometrial Cancer SPORE at MD Anderson Cancer Center are the following: 1) develop novel therapeutic strategies for advanced/recurrent endometrial cancer and aggressive subtypes; 2) promote novel strategies for unmet clinical needs in prevention and conservative therapy of high-risk precancerous lesions and low grade endometrial cancer; 3) incorporate molecular diagnostics into clinical decision-making; and 4) recruit and support new investigators in endometrial cancer research through the Career Enhancement and Developmental Research Programs. This parent proposal includes 4 translational research projects addressing scientific problems that span the breadth of endometrial cancer heterogeneity in an effort to impact as many patients as possible. Project 1, ?Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer,? includes a phase II trial using the mTOR inhibitor everolimus to improve standard conservative therapy (progestin-eluting intrauterine device) and is paired with innovative molecular profiling and pharmacologic approaches to further advance conservative treatment options. Project 2, ?CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma,? focuses on targeted therapeutics and molecular mechanisms underlying a clinically aggressive subtype of endometrioid endometrial cancer. It is hypothesized that CTNNB1 mutation and Wnt pathway activation promote immunosuppression in the tumor microenvironment, which enables tumor progression and recurrence. Project 3, ?EphA2 Targeting in Uterine Carcinoma,? focuses on the therapeutic target, EphA2, which is overexpressed in higher grade endometrioid carcinomas and serous carcinoma and is associated with poor overall survival. A phase I clinical trial will evaluate the efficacy and toxicity of a novel therapeutic (EPHARNA; developed by Project 3 investigators) that targets EphA2 by delivering short interfering RNA into tumor cells via a neutral liposome nanovehicle. Project 4, ?Rational Combinatorial Therapy in Endometrial Cancer,? will evaluate tumor molecular changes from biopsies procured during a combinatorial trial of PARP and PI3K pathway targeted therapy to identify biomarkers of benefit for patients with endometrial cancer. This is paired with implementing a testing platform to evaluate mechanisms responsible for adaptive resistance to targeted therapies in order to enable design of improved combination therapies for endometrial cancer. The proposed expansion project will elaborate upon the themes of Project 2 and examine the impact of PTEN loss and loss of CD73-generated adenosine signaling in the development of an immunosuppressive tumor microenvironment. Completion of this expansion project and Project 2 will help us to identify more precisely molecular modifiers of the local tumor microenvironment and will aid in the development of more rational immune-based therapy strategies.